EP1334143B1 - Polymers and polymerisation processes - Google Patents
Polymers and polymerisation processes Download PDFInfo
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- EP1334143B1 EP1334143B1 EP01982618A EP01982618A EP1334143B1 EP 1334143 B1 EP1334143 B1 EP 1334143B1 EP 01982618 A EP01982618 A EP 01982618A EP 01982618 A EP01982618 A EP 01982618A EP 1334143 B1 EP1334143 B1 EP 1334143B1
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F246/00—Copolymers in which the nature of only the monomers in minority is defined
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/31504—Composite [nonstructural laminate]
- Y10T428/31855—Of addition polymer from unsaturated monomers
- Y10T428/31935—Ester, halide or nitrile of addition polymer
Definitions
- the present invention relates to polymers formed from radical polymerisation of ethylenically unsaturated monomers including an ammonium phosphate ester zwitterionic monomer, and processes for producing them.
- the invention relates to emulsion polymerisation processes for forming high solids emulsions without the incorporation of non-polymerisable emulsifier, and to the use of these emulsions to biocompatibilise substrates.
- Yamaguchi et al in Makromol. Chem. (1989), 190, 1195-1205 describe an oil-in-water-emulsion polymerisation of styrene in the presence of polymerisable and non-polymerisable phosphoryl choline compounds as emulsifier.
- the latex product is stable, the non-polymerisable emulsifiers giving more regular shaped and sized spherical particles than the polymerisable emulsifiers.
- the polymerisations were conducted to form latexes having around 10 wt% solids.
- the mole percent of polymerisable emulsifier based on total monomer is around 10%.
- the base monomer on which the polymerisations were based was styrene.
- microspheres Whilst low levels of zwitterionic monomer reduced the particle size of microspheres in the latex product as compared to a process containing no such monomer, increasing the level from a mole % of 0.01, based on total monomer, to 0.5 resulted in an increase in the diameter of the microsphere of the product.
- the microspheres themselves were found to have low levels of adsorption of albumin as compared to polymethylmethacrylate polymerised in the absence of the ammonium phosphate ester zwitterionic monomer.
- the process was dependent on the choice of initiator, between potassium peroxodisulphate, and 2,2'-azobis[2-(imidazolin-2-yl)propane]dihydrochloride (ABIP).
- ABIP 2,2'-azobis[2-(imidazolin-2-yl)propane]dihydrochloride
- the ABIP initiated products were more influenced by the presence of the MPC monomer in terms of particle size and level of aggregates.
- the reaction mixture was agitated at high speed, with all monomers being included in the reaction vessel at the commencement of the polymerisation. It is not clear how the methylmethacrylate dispersed phase is maintained in suspension during the process for example with no MPC monomer.
- Hwa et al describe a copolymerisation of N,N-dimethyl-N-(2-methacryloyloxyethyl)-N-(3-sulphopropyl ammonium inner salt) (SPE), with ethyl methacrylate and acrylamide, in an aqueous continuous phase. Hwa produces a metastable oil-in-water product. He does not describe the particle size of the latex.
- SPE N,N-dimethyl-N-(2-methacryloyloxyethyl)-N-(3-sulphopropyl ammonium inner salt)
- WO-A-93/01221 we describe a range of copolymers of zwitterionic monomer with comonomers such as hydrophobic comonomers, ionic comonomers or reactive comonomers.
- the copolymers are formed by co-dissolving all the monomers into a solvent in which monomers and polymer are soluble and recovered by precipitation techniques. It is suggested that the product might be a micro emulsion but no examples of emulsion polymerisation are given.
- the polymers are used to coat substrates in order to improve their biocompatibility.
- Zwitterionic polymers made by the techniques such as are described in WO-A-93/01221, may.be blended with physically or mechanically desirable copolymers to provide blends which have good biocompatibilising properties.
- the level of zwitterionic monomer in the total blend is reduced, thereby rendering the product more cost effective than single component zwitterionic polymer products.
- Such blends are described in, for instance, WO-A-93/02652 and PCT/GB00/03985 (unpublished at the priority date of this application).
- PCT/GB00/03985 describes blends of MPC copolymers with higher alkyl methacrylate comonomers, blended with alkyl(meth)acrylate polymers.
- Such blends co-dissolved in a suitable organic solvent may be coated onto a surface to form a coating having micro-domains of relatively hydrophilic and relatively hydrophobic character.
- the blends may express higher levels of phosphorylcholine groups at the surface than in the bulk of the coating. This should allow the properties of a substrate coated with the polymer to be tailored for particular biocompatibility.
- a zwitterionic monomer is one of the ethylenically unsaturated monomers. It would furthermore be desirable to produce a copolymer of an ammonium phosphate ester zwitterionic monomer including low levels of that monomer. It would be desirable to carry out an emulsion polymerisation to produce a stable latex product having a small particle size, and low particle size distribution and which forms coatings having desirable biocompatibilising properties without using high levels of ammonium phosphate ester zwitterionic monomer.
- a mixture of ethylenically unsaturated monomers including water-insoluble monomers is polymerised in the dispersed phase of an oil-in-water emulsion in the presence of a water-soluble radical initiator, ethylenically unsaturated monomers including an ammonium phosphate ester zwitterionic monomer the process being characterised by being carried out at component concentrations to give a latex product having a polymer solids concentration of at least 20% by weight and further characterised in that the monomers comprise a zwitterionic comonomer which is a sulpho- or carboxy-betaine monomer and the weight ratio of betaine monomer to ammonium phosphate ester zwitterionic monomer is in the range (1-50):1.
- the solids concentration of the product is usually no more than 60%, preferably in the range 25 to 50% by weight.
- the process of the invention may be carried out in the presence of non-polymerisable emulsifiers and/or stabilisers. It is found that it is possible for the emulsion and latex product to be adequately stabilised by the presence of the ammonium phosphate ester zwitterionic monomer, optionally in combination with other surface active monomers. The process is preferably carried out therefore in the substantial absence of non-polymerisable surfactant/emulsifier and stabiliser.
- the ammonium phosphate ester zwitterionic monomer is preferably included in an amount in the range 0.01 to 5% by weight, based on the total weight of monomers. More preferably the level of the zwitterionic monomer is in the range 0.05 to 2% by weight, for instance 0.1 to 1% by weight.
- the ammonium phosphate ester zwitterionic monomer preferably has the general formula YBX I in which X is the ammonium phosphate ester zwitterionic group;
- the anion is closer to B than the cation.
- the cation is closer to the group B than is the anion (called hereinafter phosphobetaines).
- X is a group of the general formula II in which R 3 is alkanediyl of 1 or more, preferably 2-6 carbon atoms optionally containing one or more ethylenically unsaturated double or triple bonds, disubstituted-aryl (arylene), alkylene arylene, arylene alkylene, or alkylene aryl alkylene, cycloalkanediyl, alkylene cycloalkyl, cycloalkyl alkylene or alkylene cycloalkyl alkylene, and optionally contains one or more fluorine substituents and/or one or more functional groups; and either the groups R 4 are the same or different and each is hydrogen or alkyl of 1 to 4 carbon atoms, preferably methyl, or aryl, such as phenyl, or two of the groups R 4 together with the nitrogen atom to which they are attached form an aliphatic heterocyclic ring containing from 5 to 7 atoms, or the three groups R 4
- X may be a group of the general formula III in which the group R 5 are the same or different and each is hydrogen, C 1-4 alkyl, such as methyl, or aryl, such as phenyl; R 6 alkanediyl of 1 or more, preferably 2-6 carbon atoms optionally containing one or more ethylenically unsaturated double or triple bonds, disubstituted-aryl (arylene), alkylene arylene, arylene alkylene, or alkylene aryl alkylene, cycloalkanediyl, alkylene cycloalkyl, cycloalkyl alkylene or alkylene cycloalkyl alkylene, optionally contains one or more fluorine substituents and/or one or more functional groups; R 7 is hydrogen, or an optionally substituted C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 6-24 aryl or C 7-24 aralkyl group.
- R 7 is preferably other than hydrogen and is more preferably an unsubstituted C 1-6 alkyl, C 6-12 aryl or C 7-12 aralkyl group. Any substituents in a substituted group R 7 are usually fluorine atoms, or hydroxyl or C 1-4 alkoxy groups.
- the monomers preferably include at least 50% by weight of ethylenically unsaturated polymerisable monomers.
- suitable monomers are compounds selected from the group consisting of C 1-12 -alkyl(alk)acrylates, C 2-12 -alkyl- and -dialkyl-(alk)acrylamides, water insoluble vinyl esters or ethers, allylic compounds, maleic or fumaric esters or imides, aconitic compounds, styrenic compounds, eg styrene, and mixtures thereof.
- the choice of monomers affects the physical properties of the mixture, in particular whether the polymer particles of the product are able to coalesce after removal of water, for instance to form stable film coatings. It is preferred that the hydrophobic compounds are selected for their ability to form films at suitable temperatures for coating processes.
- hydrophobic compounds which would tend to confer different properties of hardness on the resultant polymer.
- Monomers which tend to produce hard polymers are lower alkyl(meth)acrylate especially methylmethacrylate.
- Compounds which tend to produce softer copolymers are alkylacrylates and methacrylates having straight or branched alkyl groups with at least 4 carbon atoms, such as butyl, hexyl, 2-ethylhexyl or n-octyl groups.
- the hydrophobic compound comprises a mixture of methylmethacrylate with a C 4-8 alkyl acrylate.
- the emulsion polymerisation itself and the properties of the product, especially the biocompatibility of films produced from the emulsion, are beneficially affected by incorporating a zwitterionic comonomer.
- the zwitterionic comonomer is a sulpho- or carboxy-betaine monomer.
- the zwitterionic group X 1 may have, as anion a carboxylate group, a sulphate group, a sulphonate group or a phosphonate group, preferably carboxylate or, more preferably a sulphonate group.
- the zwitterionic group X 1 may have as cationic group an ammonium, phosphonium or sulphonium group, preferably an ammonium group.
- a preferred zwitterionic,group X 1 has the general formula V where the groups R 11 are the same or different and each is hydrogen or C 1-4 alkyl and s is from 2 to 4.
- the groups R 11 are the same. It is also preferable that at least one of the groups R 11 is methyl, and more preferable that the groups R 11 are both methyl.
- s is 2 or 3, more preferably 3.
- the zwitterionic group may be an amino acid moiety in which the alpha carbon atom (to which an amine group and the carboxylic acid group are attached) is joined through a linker group to the backbone of the biocompatible polymer.
- Such groups may be represented by the general formula VI in which A 5 is a valence bond, -O-, -S- or -NH-, preferably -O-, R 12 is a valence bond (optionally together with A 5 ) or alkanediyl,-C(O)alkylene-, NHCOalkylene or -C(O)NHalkylene, preferably alkanediyl and preferably containing from 1 to 6 carbon atoms; and the groups R 13 are the same or different and each is hydrogen or alkyl of 1 to 4 carbon atoms, preferably methyl, or two or three of the groups R 13 , together with the nitrogen to which they are attached, form a heterocyclic ring of from 5 to 7 atoms, or the
- the zwitterion may be a carboxy betaine - N ⁇ (R 14 ) 2 (CH 2 ) r COO ⁇ in which the R 14 groups are the same or different and each is hydrogen or C 1-4 alkyl and r is 2 to 6, preferably 2 or 3.
- the zwitterionic group X 1 has the general formula VII W is S, PR 16 or NR 16 ; the or each groups R 16 is hydrogen or alkyl of 1 to 4 carbon atoms or the two groups R 16 together with the heteroatom to which they are attached form a heterocyclic ring of 5 to 7 atoms; R 17 is alkanediyl of 1 to 20, preferably 1 to 10, more preferably 1 to 6 carbon atoms; A 7 is a bond, NH, S or O, preferably O; and R 18 is a C 1-12 alkyl, C 7-18 aralkyl or C 6-18 aryl group or, where A 7 is other than a bond, is a C 1-12 -alkoxy, C 6-18 -aryloxy or C 7-18 -aralkoxy group.
- W is NR 16 , each R 16 is C 1-4 alkyl; and R 17 is C 2-6 alkanediyl.
- acrylic moieties are preferably methacrylic, that is in which R 8 is methyl, or acrylic, in which R 8 is hydrogen.
- the compounds may be acrylamido compounds (in which A is NR 10 ), in which case R 10 is preferably hydrogen, or less preferably, methyl, most preferably the compounds are esters, that is in which A 3 is O.
- Suitable examples of comonomer of the general formula IV are SPP and SPE.
- B 1 is most preferably an alkanediyl group. Whilst some of the hydrogen atoms of such group may be substituted by fluorine atoms, preferably B 1 is an unsubstituted alkanediyl group, most preferably a straight chain group having 2 to 6 carbon atoms.
- the ratio of the zwitterionic (butane) comonomer to ammonium phosphate ester zwitterionic monomer is in the range (1 to 50):1, preferably in the range (5 to 20):1.
- the ethylenically unsaturated monomers may further comprise hydrophilic monomer, for instance relatively water-soluble monomers.
- Hydrophilic monomers are preferably selected from the group consisting of C 1-4 -hydroxyalkyl(meth)acrylates, C 1-4 -hydroxyalkyl(meth)acrylamides, C 1-3 -alkoxy-C 2-4 -alkyl(meth)acrylates, C 1-3 -alkoxy-C 2-4 -alkyl(meth)acrylamides, C 1-3 -alkoxy-oligoethoxy(meth)acrylates, C 1-4 -dihydroxyalkyl(meth)acrylates, N-mono- or N,N- di- C 1-2 alkyl (meth)acrylamides, N-vinylactams, and C 2-4 -hydroxyalkyl-oligoethoxy(meth)acrylates and mixtures thereof.
- a hydrophilic monomer a monomer comprising an oligoethoxy moiety, that is selected from C 1-3 -alkoxy-oligoethoxy(meth)acrylates and C 2-4 -hydroxyalkyloligoethoxy(meth)acrylates, more preferably the alkoxy terminated compounds.
- an alkoxy group is methoxy or ethoxy.
- Such compounds preferably have 5 to 50 ethoxy groups, for instance in the range 10 to 20 methoxy groups.
- Oligoethoxylated polymerisable compounds improve the stability of the emulsion during the process, as well as the latex product, and may confer desirable wetting characteristics on a product polymer as well as useful biocompatibility.
- a hydrophilic monomer is preferably included in an amount in the range 0.1 to 50% by weight of total monomers, more preferably an amount in the range 1 to 25% by weight, for instance an amount in the range 5 to 20% by weight.
- An oligo ethoxylated comonomer is preferably included in an amount in the range 1 to 20% by weight, more preferably in the range 5 to 10% by weight. It is often used in conjunction with one or more other hydrophilic monomers, such that the total amount of hydrophilic monomer is in the range 5 to 50% by weight.
- the stability of the emulsion during polymerisation is found to be improved if the pH of the emulsion is maintained slightly acidic, that is has a pH less than 7, more preferably in the range 4 to 6.8, for instance about 5. Whilst the acidity may be achieved by adding a non-polymerisable acid for instance a mineral acid, to the emulsion, it is preferable to include a polymerisable acid as one of the ethylenically unsaturated monomers.
- an ethylenically unsaturated acid is selected from fumaric acid, maleic acid, vinyl sulphonic acid and styrene sulphonic acid, more preferably selected from acrylic and methacrylic acids, and is most preferably methacrylic acid.
- acidic monomer is included, it is present in an amount in the range 0.1 to 5% by weight, more preferably in the range 0.2 to 2% by weight, based on the total weight of monomers.
- Non-polymerisable components in the polymerisation mixture, for instance in the continuous aqueous phase or in the dispersed oil phase, or at the interface.
- Non-polymerisable emulsifiers and suspending agents may be included, but are preferably not included.
- Drugs, especially water-insoluble, oil-soluble drugs may be added whereby they may become absorbed in the latex particles of the product.
- the presence of cationic groups in a polymer may confer desirable binding properties either to underlying counterionically charged surfaces, or to anionic compounds which may be contacted with a surface coated with the polymer to achieve desirable results.
- Q is -N ⁇ R 22 3 , -P ⁇ R 23 3 or -S ⁇ R 23 2 in which either the groups R 22 are the same or different and each is hydrogen, alkyl of 1 to 6 carbon atoms, preferably methyl, C 1-6 hydroxyalkyl, aryl, such as phenyl, or C 7-12 aralkyl, or two of the groups R 22 together with the nitrogen atom to which they are attached form an aliphatic heterocyclic ring containing from 5 to 7 atoms, or the three groups R 22 together with the nitrogen atom to which they are attached form a fused ring structure containing from 5 to 7 atoms in each ring, and optionally one or more of the groups R 3 is substituted by a hydrophilic functional group, and the groups R 23 are the same or different and each is R 22 or a group OR 22 , where R 22 is as defined above mutatis mutandis.
- each R 22 is a C 1-4 alkyl group, preferably each R 22 being methyl.
- R 19 is either hydrogen or methyl, preferably methyl, and A 8 is preferably -O-.
- B 2 is preferably a C 2-618 alkanediyl group, more preferably a C 2-6 alkanediyl.
- Suitable cationic monomers are 2-(N,N-dimethylamino)ethyl methacrylate methyl chloride or methyl sulphate salt, and 2-(N,N-dimethyl amino) ethyl acrylate methyl chloride or methyl sulphate salt.
- a cationic monomer may be included in an amount in the range 0.1 to 25% by weight, more preferably an amount in the range 1 to 20 % by weight, most preferably in an amount in the range 2 to 15% by weight.
- Other monomers which may useful be included in the mixture include functional monomers, comprising reactive groups which are useful to provide attachment points for ligands or for underlying substrate surfaces having co-reactive functional groups, or to provide inter- or intra-molecular crosslinkability.
- Such functional groups may react with co-reactive groups derived from other functional monomers such as hydroxyl or amine group containing monomers.
- a 12 is selected from a bond, (CH 2 ) r A 13 and (CH 2 ) r SO 3 - in which r is 1 to 12;
- a 13 is selected from a bond, -O-, O-CO-, CO-O, -CO-NR 25 -, -NR 25 -CO, -O-CO-NR 25 -, and NR 25 -CO-O-;
- Q 1 is a reactive group selected from the group consisting of aldehyde groups; silane and siloxane groups containing one or more substituents selected from halogen atoms and C 1-4 -alkoxy groups; hydroxyl; amino; carboxyl; epoxy; -CHOHCH 2 Hal (in which Hal is selected from chlorine, bromine and iodine atoms); succinimido; tosylate; triflate; imidazole carbonyl amino; optionally substituted triazine groups; cinnamyl; ethylenically and acetylenically unsaturated groups; acetoacetoxy; methylol; and chloroalkylsulphone groups; acetoxy; mesylate; carbonyl di(cycloalkyl carbodiimidoyl ; and oximino.
- Preferred groups Q 1 are aldehyde, reactive silane and siloxane, amino, epoxy, CHOHCH 2 Hal (in which Hal is halogen), succimimido, tosylate, triflate, imidazolecarbonyl amino and optionally substituted triazine groups. Most preferably Q 1 is a trialkoxy silyl group, such as a trimethoxysilyl group.
- Preferred groups B 3 are C 2-18 alkanediyl, most preferably C 2-6 - alkanediyl.
- the emulsion polymerisation of the invention may be carried out in a single step, in which all of the monomers are dispersed into an aqueous continuous phase and agitation applied to form an emulsion having suitable sized droplets followed by initiation of polymerisation.
- optimum particle size distribution is achieved if a two-step process is used, in a first step of which a seed polymer is formed, and in the second step the seeds are grown.
- the seed monomers are dispersed into the aqueous phase and polymerisation is initiated.
- the remaining monomers and additional initiator are added, so that polymerisation is initiated at the seeds.
- Monomer travels from monomer droplets to the polymer seeds.
- Such a process involves the following steps: .
- the monomers from which the seed polymer is formed comprise at least a portion of the ammonium phosphate ester zwitterionic monomer which is preferably added to the polymerisation mixture in the form of an aqueous solution.
- the seed monomers must include at least a portion of the water-insoluble monomers. These monomers are dispersed into the aqueous continuous phase in the presence of the ammonium phosphate ester zwitterionic monomer whereby an emulsion of seed monomer is formed.
- Polymerisation is initiated by radical initiator by a water-soluble initiator.
- seed growth emulsion polymerisation step is then carried out by adding further monomer including at least a portion of the remaining water-insoluble monomer to the emulsion, along with further water-soluble initiator. It may be desirable for the polymer formed after the initial seed polymerisation step to have a substantially constant composition. In this case, it is desirable for a water-immiscible liquid containing the water-insoluble monomers and other compatible comonomers and for this mixture to be added in a single addition step or continuously over an extended period to the aqueous reaction mixture.
- any of the monomers selected components for the ethylenically unsaturated monomers are immiscible with the water-insoluble monomer blend, it may be desirable for the or all of the monomers of that type to be added separately to the polymerisation mixture, for instance in the form of an aqueous solution.
- the monomer blend be added over a period during which polymerisation continues to the reaction mixture, and that polymerisation be continued after all of the monomer has been added.
- initiator it is preferred for initiator to be continuously added to the reaction mixture. Preferably a portion of initiator is retained until after all of the monomer has been added to the mixture and is then included to minimise the level of residual unpolymerised monomer in the product.
- the polymerisation may be desirable for the polymerisation to form a core-shell morphology.
- Such morphologies are generally achieved by carrying out the polymerisation, generally after a seed polymerisation step, in two or more phases.
- the polymer formed in the two or more phases differs in terms of the monomers used and/or their ratios.
- Using such techniques it is possible to form a product latex in which the polymer particles have tailored characteristics with cores and shells of desired hardness, desired hydrophilicity or desired porosity.
- Such characteristics are achieved by selecting monomers according to their glass transition temperatures, hydrophilicities, or crosslinkability.
- Core/shell morphology may be achieved by changing the composition of monomers added to the polymerisation mixture during the polymerisation process.
- monomers for forming the core should be added and polymerised in the mixture before addition of monomers for forming the shell.
- a zwitterionic comonomer is included as part of the ethylenically unsaturated monomer and is added to the polymerisation mixture as a component of the aqueous initiator composition, and is preferably added continuously over a monomer feed period during which water-insoluble monomer blend is separately added to the polymerisation mixture.
- a monomer feed period is conducted for a period in the range 5 to 1200 minutes, most preferably in the range 30 to 240 minutes.
- the ammonium phosphate ester zwitterionic monomer it has been found possible to conduct the emulsion polymerisation under conditions such that high solid content latex products are formed.
- the level of polymer in the latex product is higher than 20% by weight, for instance up to 60%, preferably in the range 20 to 50% by weight, without adversely affecting the stability nor viscosity.
- Such latexes are convenient to handle. Whilst water may be evaporated from the product latex to achieve such high solids materials, or the polymer particles may be recovered by agglomeration or coagulation techniques and redissolved into water, no such steps are carried out to achieve at least 20% by weight solids latex.
- the latex may be diluted before use or compounded with other ingredients compatible with its end use, such as water, other latices or coalescing aids.
- Coalescing aids may assist in the film formation of the final product, especially where the polymer is film forming at a higher temperature than room temperature.
- a latex preservative for instance which inhibits bacterial growth or is a biocide or fungicide, suitably an alcohol such as benzyl alcohol.
- the seeded polymerisation process allows formation of a product polymer latex having very low distribution of product particle size.
- the particle size may be controlled by the levels of seed monomer, initiator and seed growth monomer, as well as the choice of the type and amount of ammonium phosphate ester zwitterionic monomer, as well as other monomer components.
- the product latex has dispersed phase with average particle diameter of less than 1 ⁇ m, more preferably less than 500 nm, most preferably in the range 100 to 400 nm.
- the polydispersity of particle size (number average over weight average diameter) is in the range 1.0 to 2.0.
- the level of initiator for these low particle size distributions is in the range 0.001 to 0.5 weight % based on solids, preferably in the range 0.01 to 0.1 weight %.
- the ratio of weight of combined seed monomer to seed growth polymer is in the range 1:99 to 99:1, preferably in the range 1:50 to 1:10.
- the latex may be desirable to add to the latex suspended particulate solids selected from organic and inorganic water-insoluble materials. Particularly preferred are suspended inorganic solids such as pigments, preferably having particle sizes less than 1 ⁇ m.
- the latex may additionally comprise dissolved or miscible components for instance to improve the storage stability of the latex, or to provide additional properties for the product of the final dried film.
- drugs may be incorporated into the latex, either by adding a suspension or an aqueous or organic solvent-based solution to the latex. Colouring agents may also be included.
- the product of the polymerisation processes may be used as a coating composition.
- a novel coating process in which such a dispersion is coated onto a substrate to form a liquid coating on a surface thereof, and water is removed from the liquid coating to form a stable solid polymer coating on the said surface.
- water is removed by evaporation although contact with precipitating solvents may also be utilised. Evaporation may be conducted at raised temperature and/or reduced pressure, and coalescing acids, such as alcohols, esters, glycols or other ethers, may be used to provide added control over film formation.
- Preferably water removal is conducted under conditions of raised temperature under which the polymer particles coalesce to form a coherent and substantially void-free, preferably clear film.
- the dried film may be subjected to additional steps such as curing, for instance by heating, especially where the monomers include a cross-linking monomer such as monomers of the general formula IX above.
- additional steps such as curing, for instance by heating, especially where the monomers include a cross-linking monomer such as monomers of the general formula IX above.
- Gamma or other e.m. radiation or ethyleneoxide treatment may also be carried out to cure and/or sterilise the film.
- the product films have particularly desirable biocompatibilising properties. They are generally used in environments in which the coated surface is contacted with aqueous liquids, generally biological liquids, for instance containing dissolved protein or suspended cells, such as bacterial or, preferably, blood cells. Preferably such liquids are selected from blood and serum.
- a substrate is biocompatibilised by coating it with a dispersion comprising the product of the process of the invention and water is removed, to leave a stable coating of solid polymer on the surface.
- the substrate coated by the coating or biocompatibilising processes is preferably the surface of a device for use in contact with biological fluids or organs, especially a device used in contact with aqueous liquids susceptible to fouling by proteins, carbohydrates, microbes or cells of higher organisms, cell culture substrates, assay devices, biosensors etc.
- the substrate is the surface of a medical device, for instance an ophthalmic device such as a contact lens, a corneal onlay or an ophthalmic implant, or is a coating on a prosthesis, a guidewire, a catheter, a drug delivery implant, a stent, a vascular graft, a blood filter or extra corporeal circuitry components
- the active drug may be incorporated into the film by being a component of the coating latex, or by contacting the coated product, before or after curing, with a suitable drug to allow absorption or adsorption in or to the film.
- the reactor charge was first loaded into the reaction vessel.
- the internal reaction temperature was raised to 75°C using a nitrogen purge for 45 minutes. Once the temperature was reached and the 45 minutes elapsed the nitrogen purge was switched to a blanket whilst stirring at 250 to 300rpm.
- the monomer seed was then added and the reaction held for 10 minutes.
- the initiator seed was then added and the reaction held for a further 10 minutes.
- the internal temperature was then raised to 85°C over a period of 30 minutes allowing for any light exotherms to occur. (These are usually in the order of 2-3°C).
- a colour change in the reactor charge ingredients was observed from a grey to a blue white colour indicating micelle formulation.
- the monomer and initiator feeds were fed simultaneously over 150 minutes at 85°C.
- the reaction was held at 85°C for a further half hour.
- the initiator mop-up feed was then added over one hour at 85°C.
- the reaction mix was then cooled to 40°C and the alcohol added.
- the reaction was held at 40°C for a further 10 minutes.
- the polymer was then filtered through an 80 ⁇ m nylon mesh and then stored as a dispersion.
- the particle size dispersion was measured by Disk centrifuge Photosedimentometry (DCP). This technique is based on Stokes Law. The number average diameter was 107 nm with a standard deviation of 31 nm and the weight average diameter was 181 nm with a standard deviation of 86 nm.
- DCP Disk centrifuge Photosedimentometry
- Example 1 The product of Example 1 was diluted with demineralised water to a concentration of 10g/l (solids).
- the coating process in each case, involved cleaning the substrates with dichloromethane then sonicating the substrates in ethanol for two minutes.
- the cleaned substrates were then coated with the diluted product latex, allowed to dry for five minuted at room temperature, then placed in an oven at 70°C for four hours to cure and cross-link the film.
- the coated substrates were subjected to various tests for biocompatibility.
- the adhesion of E. coli to the substrates was tested using the following technique: The samples were incubated with E. coli in a nutrient broth (Oxoid) for 4 or 18 hours at 37°C. The samples were washed in phosphate buffered saline and incubated with a 1% solution of bovine serum albumin in phosphate buffered saline for 1 hour. This treatment is intended to block surface portions not coated with E. coli to prevent non-specific attachment of the reagent in the next step of the process. After washing in phosphate buffered saline, the sample were incubated with rabbit E.
- the latex was used to coat a blood filter formed of polyethylene terephthate (PET).
- PET polyethylene terephthate
- the coated filter was contacted with whole blood and observed as described in WO-A-9301221.
- the product was observed under scanning electron microscope. Whilst the coated product may be seen to contaminated by high levels of deposited material, the coated filter appears to have no adhered materials.
- Example 2 The emulsion polymerisation process described in Example 1 was repeated but omitting one or more of the ammonium phosphate ester zwitterionic monomer, betaine comonomer and PEG monomer. The various latexes were analysed to determine the number average particle size and weight average particle size using the above techniques.
- the number average molecular weight following filtration of the latex product was determined to be 133 nm (standard deviation 41 nm), whilst the weight average values were 186 (78) nm.
- the particle size of the latex remained low and with a low spread (number average particle size 100(21) nm, weight average 119 (33) nm), but the coated polymer had reduced wettability as judged by determining the critical wetting surface tension on the filter of the type used in Example 2.
- ammonium phosphate ester zwitterionic monomer was omitted, there was a significant reduction in latex stability with a build up of coagulum.
- the number average particle size was measured at 151(51) nm with the weight average being 227 (96) nm.
- the number average particle size was 394(73) nm with the weight average being 433(75) nm.
- Example 1 The monomer composition and polymerisation process described above for Example 1 was adapted to incorporate 5 or 10% by weight cationic monomer as part of the mainfeed, retaining the same relative concentrations of the remaining monomers and same overall total solids content.
- the latex product was coated using the general technique desribed in Example 2 onto the filters used in Example 2.3 and tested for their critical wetting surface tension.
- the results show that the CWST for the 5% cationic polymer was raised to 65 dyne/cm, as compared to 55 for the filter coated according to Example 2 and 45 dyne/cm for the uncoated filter.
- a glass coverslip coated using the same general technique as in Example 2 was analysed by atomic force microscope for coating smoothness, thickness and the removal force.
- the average coating smoothness was 6.5 nm as compared to 4.0 nm for the uncoated glass.
- the thickness was in the range 30 to 150 nm.
- the removal force was 2.850 ⁇ N.
- the reactor was loaded with 129g of distilled water and 0.69g of MPC, following which the temperature was raised to 75°C with nitrogen purge and stirring at 270 rpm.
- the monomer seed was added (1.32g methyl methacrylate and 1.32g butyl acrylate) and after 5 minutes the initiator seed was added (0.06g ammonium persulfate (APS) in 8g water).
- reaction temperature was raised to 85°C for 30 minutes after which the core monomer feed was added (15.12g methyl methacrylate, 3.78g butyl acrylate, 0.6g ethylene glycol dimethacrylate and 0.6g methoxy-polyethylene glycol methacrylate (550Mw)) together with another initiator feed (0.21g APS, 10.5g MPC in 31g water).
- Monomer was added over approximately an hour and immediately followed by a shell feed (12.8g methyl methacrylate, 12.8g butyl acrylate, 2.3g trimethoxysilyl propyl methacrylate, 6.6g hydroxypropylmethacrylate and 3.0g of methoxy-polyethylene glycol methacrylate (550Mw) and 0.3g methacrylic acid). This was held at 85°C for a further hour before addition of an initiator spike (0.06g APS in 6.0g water) and a further 30 minutes reaction time before being cooled. The solution was filtered through glass wool to remove a small amount of coagulum from the stirrer. 1.5g benzyl alcohol was added in 3.0g water as preservative.
- the latex was cast onto a glass plate to form a tough film that was cured to an insoluble film upon heating at 70°C in an oven.
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Abstract
Description
- The present invention relates to polymers formed from radical polymerisation of ethylenically unsaturated monomers including an ammonium phosphate ester zwitterionic monomer, and processes for producing them. In particular, the invention relates to emulsion polymerisation processes for forming high solids emulsions without the incorporation of non-polymerisable emulsifier, and to the use of these emulsions to biocompatibilise substrates.
- Yamaguchi et al in Makromol. Chem. (1989), 190, 1195-1205, describe an oil-in-water-emulsion polymerisation of styrene in the presence of polymerisable and non-polymerisable phosphoryl choline compounds as emulsifier. The latex product is stable, the non-polymerisable emulsifiers giving more regular shaped and sized spherical particles than the polymerisable emulsifiers. The polymerisations were conducted to form latexes having around 10 wt% solids. The mole percent of polymerisable emulsifier based on total monomer is around 10%. The base monomer on which the polymerisations were based was styrene.
- Sugiyama et al in Polym. J. (1993) 25(5), 521-527, describe an emulsifier free radical polymerisation of ethylenically unsaturated monomers comprising methylmethacrylate, in the presence of an ethylenically unsaturated ammonium phosphate ester zwitterionic monomer, using a water-soluble initiator. The latex product had a concentration of around 10% by weight polymer. Increasing the amount of zwitterionic monomer resulted in reduced stability of the latex. Whilst low levels of zwitterionic monomer reduced the particle size of microspheres in the latex product as compared to a process containing no such monomer, increasing the level from a mole % of 0.01, based on total monomer, to 0.5 resulted in an increase in the diameter of the microsphere of the product. The microspheres themselves were found to have low levels of adsorption of albumin as compared to polymethylmethacrylate polymerised in the absence of the ammonium phosphate ester zwitterionic monomer.
- Sugiyama et al, in J. Polym. Sci., Part A (1997) 35, 3349-3357, describe oil-in-water emulsion polymerisation of methylmethacrylate, optionally with a comonomer of hydroxypropyl methacrylamide, in the presence of 2-methacryloyloxyethyl-2'-trimethylammoniumethyl phosphate inner salt (MPC). The MPC is present at a level of about 1% based on total ethylenically unsaturated monomer. The latex product had a polymer solids concentration of around 10% by weight. Again the presence of MPC resulted in a decrease in the stability of the latex product with more aggregates being formed. The process was dependent on the choice of initiator, between potassium peroxodisulphate, and 2,2'-azobis[2-(imidazolin-2-yl)propane]dihydrochloride (ABIP). The ABIP initiated products were more influenced by the presence of the MPC monomer in terms of particle size and level of aggregates. In both Sugiyama papers, the reaction mixture was agitated at high speed, with all monomers being included in the reaction vessel at the commencement of the polymerisation. It is not clear how the methylmethacrylate dispersed phase is maintained in suspension during the process for example with no MPC monomer.
- Zimehl et al, in Colloid Polym. Sci. (1990) 268, 924-933 describe emulsion polymerisation of polystyrene using potassium peroxodisulphate in the presence of N-(3-sulphopropyl)-N-methacrylomidyl propyl (N,N-dimethylammonium betaine) (SPP) at SPP concentrations in the range 5 to 70% by weight based on total monomer. The particle size of the latex product was dependent upon the initiator and the level of betaine comonomer. Again, all of the monomers were dispersed into the aqueous continuous phase before polymerisation was initiated. The solids concentration of product latex was around 10% by weight.
- In US-A-3497482 Hwa et al describe a copolymerisation of N,N-dimethyl-N-(2-methacryloyloxyethyl)-N-(3-sulphopropyl ammonium inner salt) (SPE), with ethyl methacrylate and acrylamide, in an aqueous continuous phase. Hwa produces a metastable oil-in-water product. He does not describe the particle size of the latex.
- In WO-A-93/01221 we describe a range of copolymers of zwitterionic monomer with comonomers such as hydrophobic comonomers, ionic comonomers or reactive comonomers. The copolymers are formed by co-dissolving all the monomers into a solvent in which monomers and polymer are soluble and recovered by precipitation techniques. It is suggested that the product might be a micro emulsion but no examples of emulsion polymerisation are given. The polymers are used to coat substrates in order to improve their biocompatibility. Whilst improvements in biocompatibility may be achieved by using molar percentages of 1% or lower of zwitterionic monomer, based on total ethylenically unsaturated monomer, it is often found that at least 20 mol% zwitterionic monomer is needed for satisfactory levels of improved biocompatibility. The higher the level of zwitterionic monomers, the greater the expense.
- Zwitterionic polymers made by the techniques such as are described in WO-A-93/01221, may.be blended with physically or mechanically desirable copolymers to provide blends which have good biocompatibilising properties. The level of zwitterionic monomer in the total blend is reduced, thereby rendering the product more cost effective than single component zwitterionic polymer products. Such blends are described in, for instance, WO-A-93/02652 and PCT/GB00/03985 (unpublished at the priority date of this application). PCT/GB00/03985 describes blends of MPC copolymers with higher alkyl methacrylate comonomers, blended with alkyl(meth)acrylate polymers. Such blends, co-dissolved in a suitable organic solvent may be coated onto a surface to form a coating having micro-domains of relatively hydrophilic and relatively hydrophobic character. The blends may express higher levels of phosphorylcholine groups at the surface than in the bulk of the coating. This should allow the properties of a substrate coated with the polymer to be tailored for particular biocompatibility.
- It would be desirable to produce a latex having high solids, in which a zwitterionic monomer is one of the ethylenically unsaturated monomers. It would furthermore be desirable to produce a copolymer of an ammonium phosphate ester zwitterionic monomer including low levels of that monomer. It would be desirable to carry out an emulsion polymerisation to produce a stable latex product having a small particle size, and low particle size distribution and which forms coatings having desirable biocompatibilising properties without using high levels of ammonium phosphate ester zwitterionic monomer.
- In a new emulsion polymerisation process according to the invention, a mixture of ethylenically unsaturated monomers including water-insoluble monomers is polymerised in the dispersed phase of an oil-in-water emulsion in the presence of a water-soluble radical initiator, ethylenically unsaturated monomers including an ammonium phosphate ester zwitterionic monomer the process being characterised by being carried out at component concentrations to give a latex product having a polymer solids concentration of at least 20% by weight and further characterised in that the monomers comprise a zwitterionic comonomer which is a sulpho- or carboxy-betaine monomer and the weight ratio of betaine monomer to ammonium phosphate ester zwitterionic monomer is in the range (1-50):1.
- In the new process, the solids concentration of the product is usually no more than 60%, preferably in the range 25 to 50% by weight.
- The process of the invention may be carried out in the presence of non-polymerisable emulsifiers and/or stabilisers. It is found that it is possible for the emulsion and latex product to be adequately stabilised by the presence of the ammonium phosphate ester zwitterionic monomer, optionally in combination with other surface active monomers. The process is preferably carried out therefore in the substantial absence of non-polymerisable surfactant/emulsifier and stabiliser.
- The ammonium phosphate ester zwitterionic monomer is preferably included in an amount in the range 0.01 to 5% by weight, based on the total weight of monomers. More preferably the level of the zwitterionic monomer is in the range 0.05 to 2% by weight, for instance 0.1 to 1% by weight.
- The ammonium phosphate ester zwitterionic monomer preferably has the general formula
YBX I
in which X is the ammonium phosphate ester zwitterionic group; - B is a bond, or a straight or branched alkanediyl, alkylene oxaalkylene, or alkylene (oligooxalkylene) group, optionally containing one or more fluorine substituents; and
- Y is an ethylenically unsaturated group selected from H2C=CR-CO-A-, H2C=CR-C6H4-A1-, H2C=CR-CH2A2-, R2O-CO-CR=CR-CO-O-, RCH=CH-COO-, RCH=C(COOR2)CH2-CO-O-,
- A is -O- or NR1;
- A1 is selected from a bond, (CH2)nA2 and (CH2)n SO3- in which n is 1 to 12;
- A2 is selected from a bond, -O-, O-CO-, -CO-O, -CO-NR1-, -NR1-CO, -O-CO-NR1-, and -NR1-CO-O- ;
- R is hydrogen or C1-4 alkyl;
- R1 is hydrogen, C1-4 alkyl or BX; and
- R2 is hydrogen or C1-4 alkyl.
- Generally in the zwitterionic group X, the anion is closer to B than the cation. However in some zwitterions, the cation is closer to the group B than is the anion (called hereinafter phosphobetaines).
- Preferably X is a group of the general formula II
either the groups R4 are the same or different and each is hydrogen or alkyl of 1 to 4 carbon atoms, preferably methyl, or aryl, such as phenyl, or two of the groups R4 together with the nitrogen atom to which they are attached form an aliphatic heterocyclic ring containing from 5 to 7 atoms, or the three groups R4 together with the nitrogen atom to which they are attached form a fused ring structure containing from 5 to 7 atoms in each ring, and optionally one or more of the groups R4 is substituted by a hydrophilic functional group. - Alternatively X may be a group of the general formula III
R6 alkanediyl of 1 or more, preferably 2-6 carbon atoms optionally containing one or more ethylenically unsaturated double or triple bonds, disubstituted-aryl (arylene), alkylene arylene, arylene alkylene, or alkylene aryl alkylene, cycloalkanediyl, alkylene cycloalkyl, cycloalkyl alkylene or alkylene cycloalkyl alkylene, optionally contains one or more fluorine substituents and/or one or more functional groups;
R7 is hydrogen, or an optionally substituted C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C6-24 aryl or C7-24 aralkyl group. - In a group of the general formula III, R7 is preferably other than hydrogen and is more preferably an unsubstituted C1-6 alkyl, C6-12 aryl or C7-12 aralkyl group. Any substituents in a substituted group R7 are usually fluorine atoms, or hydroxyl or C1-4 alkoxy groups.
- In the new emulsion polymerisation process the monomers preferably include at least 50% by weight of ethylenically unsaturated polymerisable monomers. Examples of suitable monomers are compounds selected from the group consisting of C1-12-alkyl(alk)acrylates, C2-12-alkyl- and -dialkyl-(alk)acrylamides, water insoluble vinyl esters or ethers, allylic compounds, maleic or fumaric esters or imides, aconitic compounds, styrenic compounds, eg styrene, and mixtures thereof.
- As is known in emulsion polymerisation techniques, the choice of monomers affects the physical properties of the mixture, in particular whether the polymer particles of the product are able to coalesce after removal of water, for instance to form stable film coatings. It is preferred that the hydrophobic compounds are selected for their ability to form films at suitable temperatures for coating processes.
- It is found that particularly desirable characteristics are achieved by using a blend of hydrophobic compounds, which would tend to confer different properties of hardness on the resultant polymer. Monomers which tend to produce hard polymers are lower alkyl(meth)acrylate especially methylmethacrylate. Compounds which tend to produce softer copolymers are alkylacrylates and methacrylates having straight or branched alkyl groups with at least 4 carbon atoms, such as butyl, hexyl, 2-ethylhexyl or n-octyl groups. Preferably the hydrophobic compound comprises a mixture of methylmethacrylate with a C4-8 alkyl acrylate.
- The emulsion polymerisation itself and the properties of the product, especially the biocompatibility of films produced from the emulsion, are beneficially affected by incorporating a zwitterionic comonomer. The zwitterionic comonomer is a sulpho- or carboxy-betaine monomer. The zwitterionic comonomer is suitably a compound of the general formula IV
Y1 B1 X1 IV
in which Y1 is an ethylenically unsaturated group selected from H2C=CR8-CO-A6-, H2C=CR8-C6H4-A3-, H2C=CR8-CH2A4-, R9O-CO-CR8=CR8-CO-O-, R8CH=CH-CO-O-, R8CH=C(COOR9)CH2-CO-O,
A3 is selected from a bond, (CH2)mA4 and (CH2)m SO3- in which m is 1 to 12;
A4 is selected from a bond, -O-, O-CO-, CO-O, -CO-NR10-, -NR10- CO, -O-CO-NR10-, and NR10-CO-O- ;
R8 is hydrogen or C1-4 alkyl;
R10 is hydrogen, C1-4- alkyl or B1X1;
R9 is hydrogen or C1-4 alkyl;
B1 is a bond, or a straight or branched alkanediyl, alkylene oxaalkylene, or alkylene (oligooxalkylene) group, optionally containing one or more fluorine substituents; and
X1 is a zwitterionic.group other than an ammonium phosphate ester. - The zwitterionic group X1 may have, as anion a carboxylate group, a sulphate group, a sulphonate group or a phosphonate group, preferably carboxylate or, more preferably a sulphonate group. The zwitterionic group X1 may have as cationic group an ammonium, phosphonium or sulphonium group, preferably an ammonium group.
- A preferred zwitterionic,group X1 has the general formula V
- Alternatively the zwitterionic group may be an amino acid moiety in which the alpha carbon atom (to which an amine group and the carboxylic acid group are attached) is joined through a linker group to the backbone of the biocompatible polymer. Such groups may be represented by the general formula VI
R12 is a valence bond (optionally together with A5) or alkanediyl,-C(O)alkylene-, NHCOalkylene or -C(O)NHalkylene, preferably alkanediyl and preferably containing from 1 to 6 carbon atoms; and
the groups R13 are the same or different and each is hydrogen or alkyl of 1 to 4 carbon atoms, preferably methyl, or two or three of the groups R13, together with the nitrogen to which they are attached, form a heterocyclic ring of from 5 to 7 atoms, or the three group R13 together with the nitrogen atom to which they are attached form a fused ring heterocyclic structure containing from 5 to 7 atoms in each ring. - Alternatively the zwitterion may be a carboxy betaine - N⊕(R14)2(CH2)rCOO⊖ in which the R14 groups are the same or different and each is hydrogen or C1-4 alkyl and r is 2 to 6, preferably 2 or 3.
- In another embodiment, the zwitterionic group X1 has the general formula VII
the or each groups R16 is hydrogen or alkyl of 1 to 4 carbon atoms or the two groups R16 together with the heteroatom to which they are attached form a heterocyclic ring of 5 to 7 atoms;
R17 is alkanediyl of 1 to 20, preferably 1 to 10, more preferably 1 to 6 carbon atoms;
A7 is a bond, NH, S or O, preferably O; and
R18 is a C1-12 alkyl, C7-18 aralkyl or C6-18 aryl group or, where A7 is other than a bond, is a C1-12-alkoxy, C6-18-aryloxy or C7-18-aralkoxy group. - In compounds comprising a group of the general formula VII, it is preferred that
W is NR16,
each R16 is C1-4 alkyl; and
R17 is C2-6 alkanediyl. - In all embodiments, in the zwitterionic comonomer of the general formula IV Y1 is preferably H2C=CR8-CO-A3 -. Such acrylic moieties are preferably methacrylic, that is in which R8 is methyl, or acrylic, in which R8 is hydrogen. Whilst the compounds may be acrylamido compounds (in which A is NR10), in which case R10 is preferably hydrogen, or less preferably, methyl, most preferably the compounds are esters, that is in which A3 is O. Suitable examples of comonomer of the general formula IV are SPP and SPE.
- In monomers of the general formula IV, especially where Y is the preferred acrylic group, B1 is most preferably an alkanediyl group. Whilst some of the hydrogen atoms of such group may be substituted by fluorine atoms, preferably B1 is an unsubstituted alkanediyl group, most preferably a straight chain group having 2 to 6 carbon atoms.
- The ratio of the zwitterionic (butane) comonomer to ammonium phosphate ester zwitterionic monomer is in the range (1 to 50):1, preferably in the range (5 to 20):1.
- The ethylenically unsaturated monomers may further comprise hydrophilic monomer, for instance relatively water-soluble monomers. Hydrophilic monomers are preferably selected from the group consisting of C1-4-hydroxyalkyl(meth)acrylates, C1-4-hydroxyalkyl(meth)acrylamides, C1-3-alkoxy-C2-4-alkyl(meth)acrylates, C1-3-alkoxy-C2-4-alkyl(meth)acrylamides, C1-3-alkoxy-oligoethoxy(meth)acrylates, C1-4-dihydroxyalkyl(meth)acrylates, N-mono- or N,N- di- C1-2 alkyl (meth)acrylamides, N-vinylactams, and C2-4-hydroxyalkyl-oligoethoxy(meth)acrylates and mixtures thereof.
- It has been found to be particularly useful to include, as a hydrophilic monomer, a monomer comprising an oligoethoxy moiety, that is selected from C1-3-alkoxy-oligoethoxy(meth)acrylates and C2-4-hydroxyalkyloligoethoxy(meth)acrylates, more preferably the alkoxy terminated compounds. Preferably an alkoxy group is methoxy or ethoxy. Such compounds preferably have 5 to 50 ethoxy groups, for instance in the range 10 to 20 methoxy groups. Oligoethoxylated polymerisable compounds improve the stability of the emulsion during the process, as well as the latex product, and may confer desirable wetting characteristics on a product polymer as well as useful biocompatibility.
- A hydrophilic monomer is preferably included in an amount in the range 0.1 to 50% by weight of total monomers, more preferably an amount in the range 1 to 25% by weight, for instance an amount in the range 5 to 20% by weight. An oligo ethoxylated comonomer is preferably included in an amount in the range 1 to 20% by weight, more preferably in the range 5 to 10% by weight. It is often used in conjunction with one or more other hydrophilic monomers, such that the total amount of hydrophilic monomer is in the range 5 to 50% by weight.
- The stability of the emulsion during polymerisation is found to be improved if the pH of the emulsion is maintained slightly acidic, that is has a pH less than 7, more preferably in the range 4 to 6.8, for instance about 5. Whilst the acidity may be achieved by adding a non-polymerisable acid for instance a mineral acid, to the emulsion, it is preferable to include a polymerisable acid as one of the ethylenically unsaturated monomers. Preferably an ethylenically unsaturated acid is selected from fumaric acid, maleic acid, vinyl sulphonic acid and styrene sulphonic acid, more preferably selected from acrylic and methacrylic acids, and is most preferably methacrylic acid.
- Where acidic monomer is included, it is present in an amount in the range 0.1 to 5% by weight, more preferably in the range 0.2 to 2% by weight, based on the total weight of monomers.
- Other compounds, especially other monomers may be included in the polymerisation mixture, for instance to achieve desired product characteristics.
- It may also be desirable to include non-polymerisable components in the polymerisation mixture, for instance in the continuous aqueous phase or in the dispersed oil phase, or at the interface. Non-polymerisable emulsifiers and suspending agents may be included, but are preferably not included. Drugs, especially water-insoluble, oil-soluble drugs may be added whereby they may become absorbed in the latex particles of the product.
- It may be desirable to include cationic monomer, in order to provide a product polymer having an overall cationic charge.
- As described in our application number WO-A-93/01221 and WO-A-98/22516, the presence of cationic groups in a polymer may confer desirable binding properties either to underlying counterionically charged surfaces, or to anionic compounds which may be contacted with a surface coated with the polymer to achieve desirable results.
- A cationic monomer is preferably a compound of the general formula VIII
Y2 B2 Q VIII
in which Y2 is an ethylenically unsaturated group selected from H2C=CR19-CO-A8-, H2C=CR19-C6H4-A9-, H2C=CR19-CH2A10, R21O-CO-CR19=CR19-CO-O-, R19CH=CH-CO-O-, R19CH=C(COOR21)CH2-CO-O-,
A9 is selected from a bond, (CH2)qA10 and (CH2)q SO3- in which q is 1 to 12;
A10 is selected from a bond, -O-, O-CO-, -CO-O, -CO-NR20-, -NR20-CO, O-CO-NR20-, and NR20-CO-O-;
R19 is hydrogen or C1-4 alkyl;
R20 is hydrogen, C1-4 alkyl or BX,
R21 is hydrogen or C1-4 alkyl;
B2 is a bond, or a straight or branched alkanediyl, alkylene oxaalkylene, or alkylene (oligooxalkylene) group, optionally containing one or more fluorine substituents; and - Q is -N⊕R22 3, -P⊕R23 3 or -S⊕R23 2 in which either the groups R22 are the same or different and each is hydrogen, alkyl of 1 to 6 carbon atoms, preferably methyl, C1-6 hydroxyalkyl, aryl, such as phenyl, or C7-12 aralkyl, or two of the groups R22 together with the nitrogen atom to which they are attached form an aliphatic heterocyclic ring containing from 5 to 7 atoms, or the three groups R22 together with the nitrogen atom to which they are attached form a fused ring structure containing from 5 to 7 atoms in each ring, and optionally one or more of the groups R3 is substituted by a hydrophilic functional group, and
the groups R23 are the same or different and each is R22 or a group OR22, where R22 is as defined above mutatis mutandis. - In the cationic monomer of the general formula VIII Q is preferably - N⊕R22 3, in which each R22 is a C1-4 alkyl group, preferably each R22 being methyl. The group Y2 is preferably an acrylic group, that is of the formula H2C=CR19COA8. In such groups R19 is either hydrogen or methyl, preferably methyl, and A8 is preferably -O-. B2 is preferably a C2-618 alkanediyl group, more preferably a C2-6 alkanediyl. Examples of suitable cationic monomers are 2-(N,N-dimethylamino)ethyl methacrylate methyl chloride or methyl sulphate salt, and 2-(N,N-dimethyl amino) ethyl acrylate methyl chloride or methyl sulphate salt.
- A cationic monomer may be included in an amount in the range 0.1 to 25% by weight, more preferably an amount in the range 1 to 20 % by weight, most preferably in an amount in the range 2 to 15% by weight.
- Other monomers which may useful be included in the mixture include functional monomers, comprising reactive groups which are useful to provide attachment points for ligands or for underlying substrate surfaces having co-reactive functional groups, or to provide inter- or intra-molecular crosslinkability. Such functional groups may react with co-reactive groups derived from other functional monomers such as hydroxyl or amine group containing monomers.
- Preferably a reactive monomer has the general formula IX
Y3 B3 Q1 IX
in which Y3 is an ethylenically unsaturated group selected from H2C=CR24-CO-A"-, H2C=CR24-C6H4-A12-, H2C=CR19-CH2A13, R26O-CO-CR24=CR-CO-O-, R24CH=CH-CO-O-, R24CH=C(COOR26)CH2-CO-O-,
A12 is selected from a bond, (CH2)rA13 and (CH2)r SO3- in which r is 1 to 12;
A13 is selected from a bond, -O-, O-CO-, CO-O, -CO-NR25-, -NR25-CO, -O-CO-NR25-, and NR25-CO-O-;
R 24 is hydrogen or C1-4 alkyl;
R25 is hydrogen, C1-4-alkyl or B3Q1 ;
R 26 is hydrogen or C1-4 alkyl;
B3 is a bond, or a straight or branched alkanediyl, alkylene oxaalkylene, or alkylene (oligooxalkylene) group, optionally containing one or more fluorine substituents.
Q1 is a reactive group selected from the group consisting of aldehyde groups; silane and siloxane groups containing one or more substituents selected from halogen atoms and C1-4-alkoxy groups; hydroxyl; amino; carboxyl; epoxy; -CHOHCH2Hal (in which Hal is selected from chlorine, bromine and iodine atoms); succinimido; tosylate; triflate; imidazole carbonyl amino; optionally substituted triazine groups; cinnamyl; ethylenically and acetylenically unsaturated groups; acetoacetoxy; methylol; and chloroalkylsulphone groups; acetoxy; mesylate; carbonyl di(cycloalkyl carbodiimidoyl ; and oximino. - Preferred groups Q1 are aldehyde, reactive silane and siloxane, amino, epoxy, CHOHCH2Hal (in which Hal is halogen), succimimido, tosylate, triflate, imidazolecarbonyl amino and optionally substituted triazine groups. Most preferably Q1 is a trialkoxy silyl group, such as a trimethoxysilyl group.
- In the reactive monomer of the general formula IX the ethylenically unsaturated group Y3 is preferably and acrylic type group, that is a group H2C=CR24A11-, R24 preferably being hydrogen or, most preferably, methyl and A11 preferably being -O-. Preferred groups B3 are C2-18 alkanediyl, most preferably C2-6- alkanediyl.
- The emulsion polymerisation of the invention may be carried out in a single step, in which all of the monomers are dispersed into an aqueous continuous phase and agitation applied to form an emulsion having suitable sized droplets followed by initiation of polymerisation. However, optimum particle size distribution is achieved if a two-step process is used, in a first step of which a seed polymer is formed, and in the second step the seeds are grown. In such a process, the seed monomers are dispersed into the aqueous phase and polymerisation is initiated. To the seed polymer latex, the remaining monomers and additional initiator are added, so that polymerisation is initiated at the seeds. Monomer travels from monomer droplets to the polymer seeds.
- Such a process involves the following steps: .
- i) at least a portion of the ammonium phosphate ester zwitterionic monomer and a portion of the initiator are added in a first stage to the aqueous continuous phase;
- ii) before, simultaneously or after step i) a monomer seed mixture comprising a portion of the water-soluble monomers is added to the aqueous continuous phase;
- iii) after both steps i) and ii) polymerisation is initiated to form emulsion-polymerised polymer seeds;
- iv) subsequently, the remaining monomers and seed growth initiator are added to the continuous phase and seed growth polymerisation carried out.
- Preferably in a process involving a seed polymerisation step, the monomers from which the seed polymer is formed comprise at least a portion of the ammonium phosphate ester zwitterionic monomer which is preferably added to the polymerisation mixture in the form of an aqueous solution. The seed monomers must include at least a portion of the water-insoluble monomers. These monomers are dispersed into the aqueous continuous phase in the presence of the ammonium phosphate ester zwitterionic monomer whereby an emulsion of seed monomer is formed. Polymerisation is initiated by radical initiator by a water-soluble initiator.
- After seed polymerisation has continued until the yield of polymer is at least 1 % based on solids, seed growth emulsion polymerisation step is then carried out by adding further monomer including at least a portion of the remaining water-insoluble monomer to the emulsion, along with further water-soluble initiator. It may be desirable for the polymer formed after the initial seed polymerisation step to have a substantially constant composition. In this case, it is desirable for a water-immiscible liquid containing the water-insoluble monomers and other compatible comonomers and for this mixture to be added in a single addition step or continuously over an extended period to the aqueous reaction mixture. If any of the monomers selected components for the ethylenically unsaturated monomers are immiscible with the water-insoluble monomer blend, it may be desirable for the or all of the monomers of that type to be added separately to the polymerisation mixture, for instance in the form of an aqueous solution.
- It is preferred that the monomer blend be added over a period during which polymerisation continues to the reaction mixture, and that polymerisation be continued after all of the monomer has been added. During the monomer feed period, it is preferred for initiator to be continuously added to the reaction mixture. Preferably a portion of initiator is retained until after all of the monomer has been added to the mixture and is then included to minimise the level of residual unpolymerised monomer in the product.
- It may be desirable for the polymerisation to form a core-shell morphology. Such morphologies are generally achieved by carrying out the polymerisation, generally after a seed polymerisation step, in two or more phases. Generally the polymer formed in the two or more phases differs in terms of the monomers used and/or their ratios. Using such techniques it is possible to form a product latex in which the polymer particles have tailored characteristics with cores and shells of desired hardness, desired hydrophilicity or desired porosity. Such characteristics are achieved by selecting monomers according to their glass transition temperatures, hydrophilicities, or crosslinkability. To achieve a low porosity product, for instance, it may be desirable to incorporate di-, tri- or higher-functional ethylenically unsaturated monomers, or to include functional monomers which may be reacted with the same or different functional monomers during or after polymerisation to provide intermolecular crosslinks.
- Core/shell morphology may be achieved by changing the composition of monomers added to the polymerisation mixture during the polymerisation process. Thus monomers for forming the core should be added and polymerised in the mixture before addition of monomers for forming the shell.
- In one particular embodiment of the process of the invention, a zwitterionic comonomer is included as part of the ethylenically unsaturated monomer and is added to the polymerisation mixture as a component of the aqueous initiator composition, and is preferably added continuously over a monomer feed period during which water-insoluble monomer blend is separately added to the polymerisation mixture. Preferably a monomer feed period is conducted for a period in the range 5 to 1200 minutes, most preferably in the range 30 to 240 minutes.
- By the use of the ammonium phosphate ester zwitterionic monomer it has been found possible to conduct the emulsion polymerisation under conditions such that high solid content latex products are formed. Thus the level of polymer in the latex product is higher than 20% by weight, for instance up to 60%, preferably in the range 20 to 50% by weight, without adversely affecting the stability nor viscosity. Such latexes are convenient to handle. Whilst water may be evaporated from the product latex to achieve such high solids materials, or the polymer particles may be recovered by agglomeration or coagulation techniques and redissolved into water, no such steps are carried out to achieve at least 20% by weight solids latex. Alternatively the latex may be diluted before use or compounded with other ingredients compatible with its end use, such as water, other latices or coalescing aids. Coalescing aids may assist in the film formation of the final product, especially where the polymer is film forming at a higher temperature than room temperature. One suitable component is a latex preservative, for instance which inhibits bacterial growth or is a biocide or fungicide, suitably an alcohol such as benzyl alcohol.
- The seeded polymerisation process allows formation of a product polymer latex having very low distribution of product particle size. The particle size may be controlled by the levels of seed monomer, initiator and seed growth monomer, as well as the choice of the type and amount of ammonium phosphate ester zwitterionic monomer, as well as other monomer components. Preferably the product latex has dispersed phase with average particle diameter of less than 1 µm, more preferably less than 500 nm, most preferably in the range 100 to 400 nm. Preferably the polydispersity of particle size (number average over weight average diameter) is in the range 1.0 to 2.0.
- It is preferred that the level of initiator for these low particle size distributions is in the range 0.001 to 0.5 weight % based on solids, preferably in the range 0.01 to 0.1 weight %. Preferably the ratio of weight of combined seed monomer to seed growth polymer is in the range 1:99 to 99:1, preferably in the range 1:50 to 1:10.
- For instance it may be desirable to add to the latex suspended particulate solids selected from organic and inorganic water-insoluble materials. Particularly preferred are suspended inorganic solids such as pigments, preferably having particle sizes less than 1 µm. The latex may additionally comprise dissolved or miscible components for instance to improve the storage stability of the latex, or to provide additional properties for the product of the final dried film. For instance, drugs may be incorporated into the latex, either by adding a suspension or an aqueous or organic solvent-based solution to the latex. Colouring agents may also be included.
- The product of the polymerisation processes may be used as a coating composition.
- According to a further aspect of the invention there is provided a novel coating process in which such a dispersion is coated onto a substrate to form a liquid coating on a surface thereof, and water is removed from the liquid coating to form a stable solid polymer coating on the said surface. Generally water is removed by evaporation although contact with precipitating solvents may also be utilised. Evaporation may be conducted at raised temperature and/or reduced pressure, and coalescing acids, such as alcohols, esters, glycols or other ethers, may be used to provide added control over film formation.
- Preferably water removal is conducted under conditions of raised temperature under which the polymer particles coalesce to form a coherent and substantially void-free, preferably clear film.
- The dried film may be subjected to additional steps such as curing, for instance by heating, especially where the monomers include a cross-linking monomer such as monomers of the general formula IX above. Gamma or other e.m. radiation or ethyleneoxide treatment may also be carried out to cure and/or sterilise the film.
- The product films have particularly desirable biocompatibilising properties. They are generally used in environments in which the coated surface is contacted with aqueous liquids, generally biological liquids, for instance containing dissolved protein or suspended cells, such as bacterial or, preferably, blood cells. Preferably such liquids are selected from blood and serum.
- According to a further aspect of the invention there is provided a novel biocompatibilising process in which a substrate is biocompatibilised by coating it with a dispersion comprising the product of the process of the invention and water is removed, to leave a stable coating of solid polymer on the surface.
- The substrate coated by the coating or biocompatibilising processes is preferably the surface of a device for use in contact with biological fluids or organs, especially a device used in contact with aqueous liquids susceptible to fouling by proteins, carbohydrates, microbes or cells of higher organisms, cell culture substrates, assay devices, biosensors etc. Most preferably the substrate is the surface of a medical device, for instance an ophthalmic device such as a contact lens, a corneal onlay or an ophthalmic implant, or is a coating on a prosthesis, a guidewire, a catheter, a drug delivery implant, a stent, a vascular graft, a blood filter or extra corporeal circuitry components
- In a drug delivery device, the active drug may be incorporated into the film by being a component of the coating latex, or by contacting the coated product, before or after curing, with a suitable drug to allow absorption or adsorption in or to the film.
- The following examples illustrate the invention:
- The following components are used in a seeded emulsion polymerisation technique as described below:
Table 1 % (g) Reactor Charge Demin water 59.79 179.37 MPC 0.23 0.69 Monomer Seed Methyl Methacrylate 0.44 1.32 Butyl Acrylate 0.44 1.32 Initiator Seed Initiator 0.02 0.06 Demin water 2.66 7.98 Monomer Feed (Controlled pumping) Methyl methacrylate 7.3 21.9 Butyl acrylate 7.3 21.9 Trimethoxysilylpropyl methacrylate 0.77 2.31 Hydroxypropyl methacrylate 2.21 6.63 MethoxyPEG methacrylate (mwt550) 1.31 3.93 Methacrylic acid 0.11 0.33 Initiator Feed (Controlled pumping) Initiator 0.07 0.21 Demin water 10.33 30.99 Dimethylammoniumpropyl sulphonate, ethyl methacrylate 3.5 10.5 Mop up Feed Demin water 2 6 Initiator 0.02 0.06 Alcohol addition Demin water 1 3 Benzyl alcohol 0.5 1.5 Total 100 300 - The reactor charge was first loaded into the reaction vessel. The internal reaction temperature was raised to 75°C using a nitrogen purge for 45 minutes. Once the temperature was reached and the 45 minutes elapsed the nitrogen purge was switched to a blanket whilst stirring at 250 to 300rpm. The monomer seed was then added and the reaction held for 10 minutes. The initiator seed was then added and the reaction held for a further 10 minutes. The internal temperature was then raised to 85°C over a period of 30 minutes allowing for any light exotherms to occur. (These are usually in the order of 2-3°C). A colour change in the reactor charge ingredients was observed from a grey to a blue white colour indicating micelle formulation.
- Once the 85°C temperature had been reached the monomer and initiator feeds were fed simultaneously over 150 minutes at 85°C. When the feed solutions had been added the reaction was held at 85°C for a further half hour. The initiator mop-up feed was then added over one hour at 85°C. The reaction mix was then cooled to 40°C and the alcohol added. The reaction was held at 40°C for a further 10 minutes. The polymer was then filtered through an 80µm nylon mesh and then stored as a dispersion.
- The particle size dispersion was measured by Disk centrifuge Photosedimentometry (DCP). This technique is based on Stokes Law. The number average diameter was 107 nm with a standard deviation of 31 nm and the weight average diameter was 181 nm with a standard deviation of 86 nm.
- The product was analysed to determine the levels of residual monomer. The results are shown in Table 2 below.
Table 2 Residual Monomer Monomer ppm methylmethacrylate <30 butylacrylate <30 methacrylic acid <5 hydroxypropylmethacrylate <25 silyl monomer <5 sulphobetaine monomer <1800 MPC <5 - The product of Example 1 was diluted with demineralised water to a concentration of 10g/l (solids). The coating process, in each case, involved cleaning the substrates with dichloromethane then sonicating the substrates in ethanol for two minutes. The cleaned substrates were then coated with the diluted product latex, allowed to dry for five minuted at room temperature, then placed in an oven at 70°C for four hours to cure and cross-link the film.
- The coated substrates were subjected to various tests for biocompatibility.
- In the first test the extent of fibrinogen adhesion to the substrate is tested using the protocol substantially as described in WO-A-9301221. The control, uncoated substrates were also tested and the levels of reduction are shown in Table 3.
Table 3 Fibrinogen Reduction (Fg) on Various Substrates Uncoated Coated Substrate Mean Absorbance @ 450nm (S.D) Glass 1.772 (0.200) 0.807 (0.074) Steel 1.756 (0.223) 0.382 (0.053) PVC 1.283 (0.227) 0.461 (0.119) PET 1.472 (0.164) 0.499 (0.067) - The adhesion of E. coli to the substrates was tested using the following technique: The samples were incubated with E. coli in a nutrient broth (Oxoid) for 4 or 18 hours at 37°C. The samples were washed in phosphate buffered saline and incubated with a 1% solution of bovine serum albumin in phosphate buffered saline for 1 hour. This treatment is intended to block surface portions not coated with E. coli to prevent non-specific attachment of the reagent in the next step of the process. After washing in phosphate buffered saline, the sample were incubated with rabbit E. coli polyclonal antibody conjugated to horseradish peroxidase (1/200) for 1 hour, washed for 10 minutes in phosphate buffered saline and incubated with a chromogenic substrate OPD (orthophenylene diamine) substrate buffer for a predetermined period in the range 10-20 minutes. The absorbance was read at 450 nm. This enzyme linked immunoassay result is recognised to correlate to the level of adhesion of E. coli cells.
- The results are shown in Table 4.
Table 4 E-Coli Reduction on Various Substrates Uncoated Coated Substrate Mean Absorbance @ 450nm (S.D) Glass 1.850 (0.173) 0.381 (0.091) Steel 0.439 (0.095) 0.184 (0.032) PVC 0.867 (0.237) 0.173 (0.091) PET 0.634 (0.282) 0.255 (0.016) - The results show that, on all four substrates, the polymers of the invention confer desirable biocompatibility as illustrated by the fibrinogen adsorption and E. coli adhesion tests.
- In a further performance test, the latex was used to coat a blood filter formed of polyethylene terephthate (PET). The coated filter was contacted with whole blood and observed as described in WO-A-9301221. The product was observed under scanning electron microscope. Whilst the coated product may be seen to contaminated by high levels of deposited material, the coated filter appears to have no adhered materials.
- The emulsion polymerisation process described in Example 1 was repeated but omitting one or more of the ammonium phosphate ester zwitterionic monomer, betaine comonomer and PEG monomer. The various latexes were analysed to determine the number average particle size and weight average particle size using the above techniques.
- It was found that the omission of the sulphobetaine monomer reduced the stability of the emulsion, resulting in some build up of coagulum. The number average molecular weight following filtration of the latex product was determined to be 133 nm (standard deviation 41 nm), whilst the weight average values were 186 (78) nm.
- For the polymer in which the PEG was omitted, the particle size of the latex remained low and with a low spread (number average particle size 100(21) nm, weight average 119 (33) nm), but the coated polymer had reduced wettability as judged by determining the critical wetting surface tension on the filter of the type used in Example 2.
- Where ammonium phosphate ester zwitterionic monomer was omitted, there was a significant reduction in latex stability with a build up of coagulum. The number average particle size was measured at 151(51) nm with the weight average being 227 (96) nm.
- Omitting both zwitterionic monomers resulted in poor particle size control as well as higher particle sizes and a bimodal distribution of particle sizes. The number average particle size was 394(73) nm with the weight average being 433(75) nm.
- Omitting both PEG based monomer and ammonium phosphate ester zwitterion again resulted in inadequate latex stability with a build up of coagulum. The measured particle sizes were number average 160(43) nm and weight average 210 (98) nm. This product also had poor critical wetting surface tension for the coated filter.
- Where both betaine monomer and PEG based monomer were omitted, inadequate latex stability was achieved with a build up of coagulum. The particle sizes were greatly increased as compared to the polymer of Example 1, with number average being 510(55) nm and the weight average being 531 (69) nm.
- Omitting both zwitterionic monomers and the PEG monomer resulted in a very poor emulsion, with very high particle sizes and particle size spreads. The number average particle size was 754(211) nm with the weight average being 1012 (382) nm.
- The monomer composition and polymerisation process described above for Example 1 was adapted to incorporate 5 or 10% by weight cationic monomer as part of the mainfeed, retaining the same relative concentrations of the remaining monomers and same overall total solids content.
- The latex product was coated using the general technique desribed in Example 2 onto the filters used in Example 2.3 and tested for their critical wetting surface tension. The results show that the CWST for the 5% cationic polymer was raised to 65 dyne/cm, as compared to 55 for the filter coated according to Example 2 and 45 dyne/cm for the uncoated filter.
- A glass coverslip coated using the same general technique as in Example 2 was analysed by atomic force microscope for coating smoothness, thickness and the removal force. The average coating smoothness was 6.5 nm as compared to 4.0 nm for the uncoated glass. The thickness was in the range 30 to 150 nm. The removal force was 2.850 µN.
- The reactor was loaded with 129g of distilled water and 0.69g of MPC, following which the temperature was raised to 75°C with nitrogen purge and stirring at 270 rpm. The monomer seed was added (1.32g methyl methacrylate and 1.32g butyl acrylate) and after 5 minutes the initiator seed was added (0.06g ammonium persulfate (APS) in 8g water). The reaction temperature was raised to 85°C for 30 minutes after which the core monomer feed was added (15.12g methyl methacrylate, 3.78g butyl acrylate, 0.6g ethylene glycol dimethacrylate and 0.6g methoxy-polyethylene glycol methacrylate (550Mw)) together with another initiator feed (0.21g APS, 10.5g MPC in 31g water). Monomer was added over approximately an hour and immediately followed by a shell feed (12.8g methyl methacrylate, 12.8g butyl acrylate, 2.3g trimethoxysilyl propyl methacrylate, 6.6g hydroxypropylmethacrylate and 3.0g of methoxy-polyethylene glycol methacrylate (550Mw) and 0.3g methacrylic acid). This was held at 85°C for a further hour before addition of an initiator spike (0.06g APS in 6.0g water) and a further 30 minutes reaction time before being cooled. The solution was filtered through glass wool to remove a small amount of coagulum from the stirrer. 1.5g benzyl alcohol was added in 3.0g water as preservative.
- The latex was cast onto a glass plate to form a tough film that was cured to an insoluble film upon heating at 70°C in an oven.
- Particle analysis of the milky white liquid showed the following characteristics of the latex:
- Helium pycnometry for average density (n=3):
- 1.1755 cm3± 0.0019 (1)
1.1727 cm3± 0.0136 (2)
1.1707 cm3± 0.0099 (3) - Disk centrifugation photosedimentometry for weight average (n=2):
- 0.1610 ± 0.045 µm (1)
0.1600 ± 0.049 µm (2) - Polydispersity (n=2):
- 1.238 (1)
1.280 (2)
Claims (45)
- An emulsion polymerisation process in which a mixture of ethylenically unsaturated monomers including water insoluble monomers are polymerised in the dispersed phase of an oil-in-water emulsion in the presence of a water-soluble radical initiator, in which the monomers comprise an ammonium phosphate ester zwitterionic monomer, characterised in that the process is carried out at concentrations to give a polymer solids concentration in the product of at least 20% by weight and in that the monomers comprise a zwitterionic comonomer which is a sulpho- or carboxy-betaine monomer and the weight ratio of betaine monomer to ammonium phosphate ester zwitterionic monomer is in the range (1-50):1.
- A process according to claim 1 in which the solids concentration of the product is up to 60% by weight.
- A process according to claim 2 in which the solids concentration is in the range 25 to 50% by weight.
- A process according to any preceding claim which is carried out in the substantial absence of non-polymerisable surfactants.
- A process according to any preceding claim in which the ammonium phosphate ester zwitterionic monomer is included in an amount in the range 0.01 to 5% by weight based on the total weight of monomers.
- A process according to claim 5 in which the ammonium phosphate ester zwitterionic monomer is included in an amount in the range 0.05 to 2% by weight.
- A process according to any preceding claim in which the ammonium phosphate ester zwitterionic monomer has the general formula I
YBX I
in which X is the ammonium phosphate ester zwitterionic group;
B is a bond, or a straight or branched alkanediyl, alkylene oxaalkylene, or alkylene (oligooxalkylene) group, optionally containing one or more fluorine substituents; and
Y is an ethylenically unsaturated group selected from H2C=CR-CO-A-, H2C=CR-C6H4-A1-, H2C=CR-CH2A2-, R2O-CO-CR=CR-CO-O-, RCH=CH-CO-O-, RCH=C(COOR2)CH2 CO-O-,
A1 is selected from a bond, (CH2)nA2 and (CH2)n SO3- in which n is 1 to 12;
A2 is selected from a bond, -O-, O-CO-, -CO-O, -CO-NR1-, -NR1-CO, -O-CO-NR1-, and -NR1-CO-O-,
R is hydrogen or C1-4 alkyl;
R1 is hydrogen, C1-4 alkyl or BX; and
R2 is hydrogen or C1-4 alkyl. - A process according to any preceding claim in which the monomers include at least 50% by weight of a hydrophobic ethylenically unsaturated polymerisable compound.
- A process according to claim 8 in which the said hydrophobic compounds are selected from C1-12 alkyl(alk)acrylates and C2-12-alkyl and di-alkyl (alk)acrylamides, styrene, and mixtures thereof.
- A process according to claim 1 in which the comonomer is a sulphobetaine monomer.
- A process according to any preceding claim in which weight ratio of betaine monomer to ammoinium phosphate ester zwitterionic monomer is in the range (5-20):1.
- A process according to any preceding claim in which the monomers comprisei) 0.1 to 25 weight% of an ammonium phosphate ester zwitterionic monomer,ii) 0.1 to 25 weight% of the betaine comonomer; andiii) 25 to 99% of a hydrophobic monomer.
- A process according to claim 12 in which the zwitterionic comonomer has the general formula IV
Y1 B1 X1 IV
in which Y1 is an ethylenically unsaturated group selected from H2C=CR8-CO-A6-, H2C=CR8-C6H4-A3-, H2C=CR8-CH2A4-, R9O-CO-CR8=CR8-CO-O-, R8CH=CH-CO-O-, R8CH=C(COOR9)CH2-CO-O,
A3 is selected from a bond, (CH2)mA4 and (CH2)m SO3- in which m is 1 to 12;
A4 is selected from a bond, -O-, O-CO-, CO-O, -CO-NR10-, -NR10- CO, - O-CO-NR10-, and NR10-CO-O-;
R8 is hydrogen or C1-4 alkyl;
R10 is hydrogen, C1-4 alkyl or B1X1;
R9 is hydrogen or C1-4 alkyl;
B1 is a bond, or a straight or branched alkanediyl, alkylene oxaalkylene, or alkylene (oligooxalkylene) group, optionally containing one or more fluorine substituents; and
X1 is a zwitterionic group. - A process according to any preceding claim in which the monomers comprise a further hydrophilic monomer
- A process according to claim 15 in which the hydrophilic monomer is selected from C2-4-hydroxyalkyl(meth)acrylates, C1-4-hydroxyalkyl(meth)acrylamides, C1-3-alkoxy-C2-4-alkyl(meth)acrylates, C1-3-alkoxy-C2-4-alkyl(meth)acrylamides. C1-3-alkoxy-oligoethoxy(meth)acrylates C1-4 -dihydroxyalkyl(meth)acrylates, N-mono- or N,N- di- C1-2 alkyl (meth)acrylamides, N-vinylactams and C2-4 hydroxyalkyl oligoethoxy(meth)acrylates, and mixtures thereof.
- A process according to claim 15 or 16 in which the said hydrophilic monomer is included in an amount in the range 0.1 to 50% by weight, based on the total weight of monomer.
- A process according to claim 17 in which the amount of hydrophilic monomer is in the range 1 to 25% by weight.
- A process according to claim 17 in which the amount of hydrophilic monomer is in the range 5 to 20% by weight.
- A process according to any preceding claim in which the monomers include an acidic monomer.
- A process according to claim 20 in which the acidic monomer is included in an amount to confer an acidic pH on the polymerisation mixture.
- A process according to claim 20 or 21 in which the acidic monomer is acrylic acid or methacrylic acid, and is present in an amount in the range 0.1 to 5% by weight based on the total weight of monomers.
- A process according to claim 22 in which the acidic monomer is present in an amount in the range 0.2 to 2% by weight.
- A process according to any preceding claim in which the monomers include a cationic monomer, of the general formula VIII
Y2 B2 Q VIII
in which Y2 is an ethylenically unsaturated group selected from H2C=CR19-CO-A8-, H2C=CR19-C6H4-A9-, H2C=CR19-CH2A10, R21O-CO-CR19=CR19-CO-O-, R19CH=CH-CO-O-, R19CH=C(COOR21)CH2-CO-O-,
A9 is selected from a bond, (CH2)qA10 and (CH2)q SO3- in which q is 1 to 12;
A10 is selected from a bond, -O-, O-CO-, -CO-O, -CO-NR20-, -NR20-CO, O-CO-NR20-, and NR20-CO-O-;
R19 is hydrogen or C1-4 alkyl;
R20 is hydrogen, C1-4 alkyl or BX;
R21 is hydrogen or C1-4 alkyl ;
B2 is a bond, or a straigh or branched alkanediyl, alkylene oxaalkylene, or alkylene (oligooxalkylene) group, optionally containing one or more fluorine substituents; and
Q is -N⊕R22 3, P⊕R23 3 or -S⊕R23 2 in which either the groups R22 are the same or different and each is hydrogen, alkyl of 1 to 6 carbon atoms, preferably methyl, C1-6 hydroxyalkyl, aryl, such as phenyl, or C7-12 aralkyl; or two of the groups R22 together with the nitrogen atom to which they are attached form an aliphatic heterocyclic ring containing from 5 to 7 atoms, or the three groups R22 together with the nitrogen atom to which they are attached form a fused ring structure containing from 5 to 7 atoms in each ring, and optionally one or more of the groups R3 is substituted by a hydrophilic functional group, and
the groups R23 are the same or different and each is R22 or a group OR22, where R22 is as defined above mutatis mutandis. - A process according to claim 24 in which the cationic monomer is selected from quaternary ammonium alkyl(alk)acrylates and - (alk)acrylamides.
- A process according to any preceding claim in which the monomers further include a reactive monomer having the general formula IX
Y3 B3 Q1 IX
in which Y3 is an ethylenically unsaturated group selected from H2C=CR24-CO-A"-, H2C=CR24-C6H4-A12-, H2C=CR19-CH2A13, R26O-CO-CR24=CR-CO-O-, R24CH=CH-CO-O-, R24CH=C(COOR26)CH2-CO-O-,
A12 is selected from a bond, (CH2)rA13 and (CH2), SO3- in which r is 1 to 12;
A13 is selected from a bond, -O-, O-CO-, CO-O, -CO-NR25-, -NR25-CO, - O-CO-NR25-, and NR25-CO-O- ;
R24 is hydrogen or C1-4 alkyl;
R25 is hydrogen, C1-4- alkyl or B3Q1;
R26 is hydrogen or C1-4 alkyl,
B3 is a bond, or a straight or branched alkanediyl, alkylene oxaalkylene, or alkylene (oligooxalkylene) group, optionally containing one or more fluorine substituents.
Q1 is a reactive group selected from the group consisting of aldehyde groups; silane and siloxane groups containing one or more substituents selected from halogen atoms and C1-4-alkoxy groups; hydroxyl; amino; carboxyl; epoxy; -CHOHCH2Hal (in which Hal is selected from chlorine, bromine and iodine atoms); succinimido; tosylate; triflate; imidazole carbonyl amino; optionally substituted triazine groups; cinnamyl; ethylenically and acetylenically unsaturated groups; acetoacetoxy; methylol; and chloroalkylsulphone groups; acetoxy; mesylate; carbonyl di(cycloalkyl carbodiimidoyl; and oximino; preferably Q1 is a trialkoxy silyl group. - A process according to any preceding claim comprising the following steps:i) at least a portion of the ammonium phosphate ester zwitterionic monomer and a portion of the initiator are added in a first stage to the aqueous continuous phase;ii) before, simultaneously or after step i) a monomer seed mixture comprising a portion of the water-soluble monomers is added to the aqueous continuous phase;iii) after both steps i) and ii) polymerisation is initiated to form emulsion-polymerised polymer seeds;iv) subsequently, the remaining monomers and seed growth initiator are added to the continuous phase and seed growth polymerisation carried out.
- A process according to claim 27 in which the composition of the combination of monomer seed mixture and zwitterionic monomer polymerised in step iii) is different to the composition of the seed growth monomers added in step iv.
- A process according to claim 28 in which the monomer seed mixture consists substantially only of hydrophobic compounds as defined in claim 8 or claim 9.
- A process according to claim 28 or claim 29 in which the seed growth monomers added in step iv) comprise any residual ammonium phosphate ester zwitterionic monomer, the residual portion of water-insoluble monomer, and optionally water-soluble monomers.
- A process according to any of claims 27 to 30 in which at least a portion of seed growth monomers are premixed before being added to the continuous phase in step iv.
- A process according to claim 31 in which the premixed seed growth monomers are continuously fed into the continuous phase over a monomer feed period during which polymerisation continues.
- A process according to claim 32 in which the monomer feed period is in the range 5 to 1200 minutes.
- A process according to claim 32 in which the monomer feed period is in the range 30 to 240 minutes.
- A process according to any of claims 32 to 34 in which an initiator feed, comprising at least a portion of the remaining initiator, is continuously fed into the continuous phase throughout the monomer feed period.
- A process according to any of claims 32 to 35 in which a portion of initiator is added after all the premixed seed growth monomer has been added to the continuous phase under conditions such that radicals are formed from the initiator.
- A process according to claim 35 in which the initiator feed comprises water-soluble monomer.
- A process according to claim 37 in which the initiator feed comprises the zwitterionic comonomer.
- A coating process in which a dispersion comprising the product of a process according to any preceding claim and optionally further comprising suspended particulate solids selected from organic and inorganic water-insoluble materials is coated onto a substrate to form a liquid coating on a surface thereof, and water is removed from the liquid coating to form a stable solid polymer coating on the said surface.
- A coating process according to claim 39 in which the water is removed by evaporation and the polymer particles coalesce during the evaporation of water to form a solid polymer film on the surface.
- A coating process according to claim 39 or claim 40 in which the surface bearing the solid polymer coating is contacted with an aqueous liquid.
- A coating process according to claim 41 in which said aqueous liquid is a biological liquid.
- A process according to claim 42 in which the biological liquid is selected from blood and serum.
- A biocompatibilising process in which a substrate is biocompatibilised by coating it with a dispersion comprising the product of a process according to any of claims 1 to 38 and optionally further comprising suspended particulate solids selected from organic and inorganic water-insoluble materials and removing the water to leave a stable coating of solid polymer on the surface.
- A medical device having a coated surface produced by a process according to any of claims 39 to 44.
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AT (1) | ATE353924T1 (en) |
AU (1) | AU2002214160A1 (en) |
DE (1) | DE60126641T2 (en) |
WO (1) | WO2002040558A1 (en) |
Families Citing this family (24)
Publication number | Priority date | Publication date | Assignee | Title |
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GB0100761D0 (en) | 2001-01-11 | 2001-02-21 | Biocompatibles Ltd | Drug delivery from stents |
US7781498B2 (en) * | 2003-07-03 | 2010-08-24 | Mallard Creek Polymers, Inc. | Cationic latex as a carrier for bioactive ingredients and methods for making and using the same |
BE1015823A3 (en) * | 2003-12-17 | 2005-09-06 | Ct Rech Metallurgiques Asbl | Process for coating a surface by metal layer ultrafine. |
US20050208093A1 (en) * | 2004-03-22 | 2005-09-22 | Thierry Glauser | Phosphoryl choline coating compositions |
US9498563B2 (en) * | 2004-04-23 | 2016-11-22 | Boston Scientific Scimed, Inc. | Medical articles having therapeutic-agent-containing regions formed from coalesced polymer particles |
EP2097119A4 (en) * | 2006-11-21 | 2012-10-17 | Abbott Lab | Use of a terpolymer of tetrafluoroethylene, hexafluoropropylene, and vinylidene fluoride in drug eluting coatings |
US20090263346A1 (en) * | 2006-12-05 | 2009-10-22 | David Taft | Systems and methods for delivery of drugs |
US20090246155A1 (en) * | 2006-12-05 | 2009-10-01 | Landec Corporation | Compositions and methods for personal care |
US8399007B2 (en) * | 2006-12-05 | 2013-03-19 | Landec Corporation | Method for formulating a controlled-release pharmaceutical formulation |
US20100004124A1 (en) * | 2006-12-05 | 2010-01-07 | David Taft | Systems and methods for delivery of materials for agriculture and aquaculture |
EP2500015A1 (en) * | 2006-12-05 | 2012-09-19 | Landec Corporation | Delivery of drugs |
WO2009070147A1 (en) | 2007-11-30 | 2009-06-04 | Hewlett-Packard Development Company, L.P. | Steric stabilized latex particulates |
US8114883B2 (en) * | 2007-12-04 | 2012-02-14 | Landec Corporation | Polymer formulations for delivery of bioactive materials |
KR101429801B1 (en) * | 2011-06-03 | 2014-08-19 | 주식회사 엘지화학 | Impact modifier for polymethylmetacrylate resin having excellent impact strength and transparency and method of preparing the same |
US8980956B2 (en) * | 2011-09-01 | 2015-03-17 | Vertellus Specialities Inc. | Methods for producing biocompatible materials |
US9006305B2 (en) | 2011-09-01 | 2015-04-14 | Vertellus Specialties Inc. | Biocompatible material |
GB201119363D0 (en) * | 2011-11-10 | 2011-12-21 | Vertellus Specialities Inc | Polymerisable material |
WO2014039495A1 (en) | 2012-09-05 | 2014-03-13 | University Of Miami | Novel keratoprosthesis, and system and method of corneal repair using same |
CN111632578A (en) * | 2013-04-01 | 2020-09-08 | 西托索尔本茨公司 | Hemocompatibility modifier for crosslinked polymeric materials |
CN103193927B (en) * | 2013-04-27 | 2016-01-20 | 南京构友生物材料有限公司 | The friendly polymkeric substance of bonding blood and method for making thereof and purposes |
DE102013220238B4 (en) | 2013-10-08 | 2015-11-12 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Device and method for the production of embolisate particles and embolisate particles |
KR20180090275A (en) * | 2015-12-21 | 2018-08-10 | 가부시키가이샤 오사카소다 | Binders, electrodes, and batteries for battery electrodes |
CN109641994B (en) * | 2016-08-25 | 2021-07-09 | 泰尔茂株式会社 | Hydrophilic copolymer and medical device |
WO2021188914A1 (en) * | 2020-03-20 | 2021-09-23 | Arkema Inc. | Vinyl acrylic emulsion copolymer and use thereof in stain resistant coating compositions |
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US3497482A (en) * | 1963-10-14 | 1970-02-24 | Rohm & Haas | Polymers of quaternary ammonium compounds |
US5364757A (en) | 1990-05-21 | 1994-11-15 | Administrators Of The Tulane Educational Fund | Methods of supporting a diagnosis of systemic lupus erythematosus |
US5739236A (en) | 1991-04-24 | 1998-04-14 | Biocompatibles Limited | Biocompatible zwitterion polymers |
US6090901A (en) | 1991-07-05 | 2000-07-18 | Biocompatibles Limited | Polymeric surface coatings |
US6225431B1 (en) | 1991-07-05 | 2001-05-01 | Biocompatibles Limited | Biocompatibilizing process |
US5705583A (en) | 1991-07-05 | 1998-01-06 | Biocompatibles Limited | Polymeric surface coatings |
CA2112411C (en) | 1991-07-05 | 2001-01-02 | Roderick W. J. Bowers | Polymeric surface coatings |
GB9226791D0 (en) | 1992-12-23 | 1993-02-17 | Biocompatibles Ltd | New materials |
FR2717818B1 (en) * | 1994-03-25 | 1996-06-07 | Rhone Poulenc Chimie | Zwitterionic latex. |
US6087462A (en) | 1995-06-07 | 2000-07-11 | Biocompatibles Limited | Polymeric surface coatings |
EP1189956B1 (en) | 1999-05-27 | 2003-07-23 | Biocompatibles UK Limited | Polymer solutions |
GB9924502D0 (en) | 1999-10-15 | 1999-12-15 | Biocompatibles Ltd | Polymer blend materials |
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- 2001-11-14 EP EP01982618A patent/EP1334143B1/en not_active Expired - Lifetime
- 2001-11-14 WO PCT/GB2001/005030 patent/WO2002040558A1/en active IP Right Grant
- 2001-11-14 DE DE60126641T patent/DE60126641T2/en not_active Expired - Lifetime
- 2001-11-14 AU AU2002214160A patent/AU2002214160A1/en not_active Abandoned
- 2001-11-14 AT AT01982618T patent/ATE353924T1/en not_active IP Right Cessation
- 2001-11-15 US US09/987,721 patent/US6780930B2/en not_active Expired - Lifetime
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2004
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DE60126641T2 (en) | 2008-02-07 |
US20040236013A1 (en) | 2004-11-25 |
ATE353924T1 (en) | 2007-03-15 |
US6780930B2 (en) | 2004-08-24 |
DE60126641D1 (en) | 2007-03-29 |
US6867257B2 (en) | 2005-03-15 |
WO2002040558A1 (en) | 2002-05-23 |
EP1334143A1 (en) | 2003-08-13 |
AU2002214160A1 (en) | 2002-05-27 |
US20020146581A1 (en) | 2002-10-10 |
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